The neuroendocrine and immune systems communicate bi-directionally. There are no accepted markers to measure their interactions, or disorders. Neuropeptide hormones and cytokines regulate cells of both systems, but little is known of the intracellular steps between binding to the surface receptors and cellular responses when cytokines and neuropeptides cross systems. The goal of this project is to begin to understand how these multiple signals are integrated at the intracellular level and subsequently alter immune and/or neuroendocrine cell function. Preliminary data suggest that the signal pathways converge and mutually affect the activity of the transcription factor, Nf-kappaB. The project is divided into three aims to investigate whether Nf-kappaB has a pivotal role in the integration of immune and neuroendocrine system signals. 1) Gel shift studies will determine the extent and specificity of neuropeptide hormones and cytokines to affect Nf-kappB in lymphoid and neuroendocrine cells. 2) A luciferase cis-reporter gene system will be used to measure changes in Nf-kappaB activity due to individual and multiple neuropeptide and cytokine signal molecules. Also, specific inhibitors of the Nf-kappaB pathway will be used to determine in a quantitative manner the effect modulating this transcription factor has on in vitro antibody and cytokine production. 3) Finally, studies using a Nf-kappaB1 gene knockout mouse model will be used for studies of the relative importance of this Nf-kappaB component for neuropeptide and cytokine effects on lymphoid and pituitary functioning. These studies will show the impact and specificity of the Nf-kappaB pathway in mediating selected neuropeptide and cytokine regulation of immune and neuroendocrine interactions. Inhibitors of Nf-kappaB are being developed, primarily as anti-inflammatory agents. Understanding the role of Nf-kappaB in neuroendocrine-immune interactions may suggest novel markers and therapeutic targets. In turn, these might have great impact for treatment of diseases involving the nervous and immune systems, such as myasthenia gravis or multiple sclerosis.